These projects use a systems biology approach (using genomic, proteomic, and bioinformatic methods) to gain a greater insight into how metabolic function changes during life-span. This will involve conducting multiple tissue analyses on organs that are known to play a role in controlling metabolic function, such as: hypothalamus, pituitary gland, tongue, gut, pancreas, liver, adipose tissue, muscle, and gonads. Once we gain a greater insight into alterations in the metabolic/energy homeostasis super-axis during the aging process, we can then elucidate which pharmacological endocrine axes targets could be best used to enhance metabolic health. Pluripotent therapeutics that are targeted towards multiple aspects of the super-axis are likely to have much greater efficacy than those that target just one aspect in isolation. We aim to elucidate and characterize - at a systemic level - endocrine regulation and feedback during the aging process, with special attention to euglycemic control axes and how these major energy axes may act as a master integrator for additional endocrine axes such as the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. Therefore, multiple dietary, digestive and reproductive axes can be integrated at the humoral level to form a higher order super-axis. Many of the hormones that create the complex feedback loops in this super-axis provide a multi-level connection between cognitive appreciation of food supply, energy sensation/perception and eventual energy metabolism. Using animal models of aging or metabolic pathophysiology (e.g. type 2 diabetes, metabolic syndrome, Alzheimers disease) we will use various genomic, proteomic, bioinformatic and behavioral approaches to model and predict complex endocrine feedback loops and determine which pharmacological endocrine axes targets could be best used to enhance metabolic health and improve health-span during the aging process.